Narrative Review

Pulmonary Hypertension in CKD

Davide Bolignano, MD,1,2 Stefania Rastelli, MD,1,2 Rajiv Agarwal, MD,3

Danilo Fliser, MD,4 Ziad Massy, MD,5,6,7 Alberto Ortiz, MD,8,9,10 Andrzej Wiecek, MD,11

Alberto Martinez-Castelao, MD,12,13 Adrian Covic, MD,14,15 David Goldsmith, MD,16

Gultekin Suleymanlar, MD,17 Bengt Lindholm, MD,18 Gianfranco Parati, MD,19,20,21

Rosa Sicari, MD,22 Luna Gargani, MD,22 Francesca Mallamaci, MD,1,2

Gerard London, MD,23,24 and Carmine Zoccali, MD1,2

Pulmonary arterial hypertension is a rare disease often associated with positive antinuclear antibody andhigh mortality. Pulmonary hypertension, which rarely is severe, occurs frequently in patients with chronickidney disease (CKD). The prevalence of pulmonary hypertension ranges from 9%-39% in individuals withstage 5 CKD, 18.8%-68.8% in hemodialysis patients, and 0%-42% in patients on peritoneal dialysis therapy.No epidemiologic data are available yet for earlier stages of CKD. Pulmonary hypertension in patients withCKD may be induced and/or aggravated by left ventricular disorders and risk factors typical of CKD, includingvolume overload, an arteriovenous fistula, sleep-disordered breathing, exposure to dialysis membranes,endothelial dysfunction, vascular calcification and stiffening, and severe anemia. No specific intervention trialaimed at reducing pulmonary hypertension in patients with CKD has been performed to date. Correctingvolume overload and treating left ventricular disorders are factors of paramount importance for relievingpulmonary hypertension in patients with CKD. Preventing pulmonary hypertension in this population is crucialbecause even kidney transplantation may not reverse the high mortality associated with established pulmonaryhypertension.Am J Kidney Dis. xx(x):xxx. © 2012 by the National Kidney Foundation, Inc.

INDEX WORDS: Pulmonary hypertension; chronic kidney disease; hemodialysis; peritoneal dialysis.

During the last 2 decades, evidence has accrueddocumenting that mild to moderate forms of

pulmonary hypertension are much more common thantraditionally has been thought.1 These forms oftenremain undetected because the disease has a longpreclinical asymptomatic phase and pulmonary hyper-tension often is suspected only when the clinical signsand symptoms of right ventricular dysfunction, namelyprogressively worsening fatigue, dyspnea, and syn-cope, are manifest.2 It increasingly is being recog-nized that pulmonary hypertension in patients withchronic kidney disease (CKD) is not confined to thosewith connective tissue and systemic diseases and thatthe decrease in kidney function per se may be a trigger

From the 1Nephrology, Dialysis and Transplantation Unit and2CNR-IBIM Clinical Epidemiology and Pathophysiology of RenalDiseases and Hypertension, Reggio Calabria, Italy; 3IndianaUniversity and Veterans Affairs Medical Center, Indianapolis, IN;4Department of Internal Medicine IV, Saarland University MedicalCentre, Homburg/Saar, Germany; 5INSERM U-1088; 6Universityof Picardie-Jules Verne; 7Division of Clinical Pharmacology andNephrology, Amiens University Hospital, Amiens, France; 8IIS-Fundación Jiménez Díaz; 9Universidad Autónoma de Madrid;10Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain; 11De-partment of Nephrology, Endocrinology and Metabolic Diseases,Medical University of Silesia, Katowice, Poland; 12Hospital Uni-versitario de Bellvitge; 13L’Hospitalet de Llobregat, Barcelona,Spain; 14T. Popa University of Medicine and Pharmacy, Iasi,Romania; 15Clinic of Nephrology, C.I. Parhon University Hospital;16Renal Unit, Guy’s and St Thomas’ NHS Foundation Hospital,

London, United Kingdom; 17Nephrology Division, Department of

Am J Kidney Dis. 2012;xx(x):xxx

for the development of this disturbance. Here, wefocus on the clinical epidemiology of pulmonaryhypertension in patients with CKD in a frameworkthat considers the World Health Organization (WHO)criteria for classifying the disease, as well as therelationship between the prevalence of this conditionand CKD staging.

DIAGNOSTIC CRITERIA

The WHO classifies pulmonary hypertension into 5categories1 (Table 1). Strictly speaking, pulmonaryhypertension is a syndrome characterized by the pres-ence of mean pulmonary artery pressure �25 mm Hgat rest as measured at right-sided cardiac catheteriza-

Medicine, Akdeniz University Medical School, Antalya, Turkey; 18Di-visions of Baxter Novum and Renal Disease, Department of ClinicalScience, Intervention and Technology, Karolinska Institutet, Stock-holm, Sweden; 19Department of Clinical Medicine and Prevention,University of Milano-Bicocca; 20Department of Cardiology, S. LucaHospital; 21Istituto Auxologico Italiano, Milan; 22CNR, Institute ofClinical Physiology, Pisa, Italy; 23INSERM U970; and 24HopitalEuropéen Georges Pompidou, Paris, France.

Received May 14, 2012. Accepted in revised form July 27, 2012.

Address correspondence to Carmine Zoccali, MD, CNR-IBIM,Clinical Epidemiology and Physiopathology of Renal Diseasesand Hypertension of Reggio Calabria, 89124, Reggio Calabria,Italy. E-mail: carmine.zoccali@tin.it

© 2012 by the National Kidney Foundation, Inc.0272-6386/$36.00

http://dx.doi.org/10.1053/j.ajkd.2012.07.029

1

ion; W

Bolignano et al

tion.2 In addition, for the diagnosis of pulmonaryartery hypertension, formerly called precapillary pul-monary hypertension (group I in the WHO classifica-tion1), pulmonary wedge pressure should be �15 mmHg and pulmonary vascular resistance should be �3Woods units.2 Noninvasive estimates of pulmonarypressure also can be made by Doppler echocardiogra-phy studies. However, the diagnosis of pulmonaryhypertension and particularly the diagnosis of pulmo-nary artery hypertension require right-sided cardiaccatheterization. In Doppler echocardiography studies,measurement of pulmonary artery systolic pressure(PASP) is based on the tricuspid regurgitation jet, aphenomenon that can be recorded in most physiologicand pathologic conditions. In the absence of pulmo-nary stenosis, right ventricular systolic pressure PASPis estimated by the calculation of right ventricularsystolic pressure by a modified Bernoulli equationand is computed as 4 times the square of maximumtricuspid regurgitation jet velocity (TRV), plus rightatrial pressure (which in turn can be estimated fromthe vena cava diameter and degree of its inspiratorycollapse).3 Often, a fixed estimate of right atrial pres-sure is added when the inferior vena cava is notevaluated during echocardiography. In Doppler echo-cardiography studies, the presence of pulmonary hy-pertension is considered most probable when PASP is�50 mm Hg and/or TRV is faster than 3.4 m/s. PASPvalues of 35-49 and TRV values of 2.8-3.4 m/s areconsidered to suggest but not to diagnose pulmonaryhypertension. It is important to emphasize that al-though superior to clinical history and physical exami-nation,4,5 Doppler measurements of pulmonary pres-sure may be inaccurate when the tricuspid regurgitationjet is difficult to visualize.6 Moreover, even whentechnically feasible, the method’s estimates of pulmo-nary pressure frequently may be inaccurate.6 Otherechocardiographic parameters (namely right ventricu-

Table 1. WHO Diagnostic Clas

Class Definition

I Idiopathic, familial, and associated PAH

II PH associated with left-sided heart disease

III PH associated with lung diseases and/or hypoxia

IV Chronic thromboembolic PH

V PH with unclear or multifactorial causes

Note: Class I PH formerly was referred to as precapillary PH; cAbbreviations: CKD, chronic kidney disease; COPD, chronic

PAH, pulmonary arterial hypertension; PH, pulmonary hypertens

lar size, thickness, and function; right and left atrial

2

volume; left ventricle systolic and diastolic function;valve anatomy and functioning; and assessment of thepresence of pericardial effusion) provide usefulcomplementary information for the diagnosis andprognostic appraisal of pulmonary hypertension.1 Thestrengths and limitations of Doppler echocardiogra-phy for the diagnosis of pulmonary hypertension arereviewed elsewhere.7

EPIDEMIOLOGY OF PULMONARY HYPERTENSION

General Population

Information about pulmonary hypertension at thecommunity level is based mainly on the OlmstedCounty study, a cohort study in a random sample ofthe general population of one county.8 In individualsolder than 45 years in this population, the prevalenceof pulmonary hypertension, defined as Doppler-derived PASP �35 mm Hg, was �5%. Most casesdetected in Olmsted County were related to underly-ing left ventricular (LV) disorders: PASP was associ-ated with both systemic hypertension and high pulsepressure and with diastolic dysfunction as measuredby the E/e= ratio (early transmitral flow velocity [E] toearly mitral annular tissue velocity [e=]). The preva-lence of pulmonary artery hypertension of the WHOclass I diagnostic category, which includes a varietyof diseases ranging from sporadic and idiopathicpulmonary hypertension to pulmonary hypertensionattributable to connective tissue diseases, drugs, andvarious toxic agents, is much more rare at around 15cases per million.1 In this diagnostic category, theprevalence of pulmonary artery hypertension relatedto background diseases is 7%-12% in systemic sclero-sis,9,10 2%-6% in portal hypertension,11,12 and �30%in congenital heart disease.13 Pulmonary hypertensionis exceedingly prevalent (15%-20%) in patients withsleep apnea (WHO diagnostic category III).14 A large

tion of Pulmonary Hypertension

Conditions

nective tissue diseases, HIV infection, congenital heart disease,rtal hypertension and pulmonary veno-occlusive disease, drugsd toxins

sided heart systolic dysfunction, left-sided heart diastolicsfunction, left-sided valvular disease (mitral and/or aortic)

D, interstitial lung disease, sleep apnea

truction of pulmonary arterial vessels (proximal or distal) byromboemboli, tumors, or foreign bodies

sis-dependent CKD; several hematologic, systemic, andetabolic disorders; miscellaneous

I, as postcapillary PH.ctive pulmonary disease; HIV, human immunodeficiency virus;HO, World Health Organization.

sifica

Conpoan

Left-dy

COP

Obsth

Dialym

lass Iobstru

survey in the United States that registered data for all

Am J Kidney Dis. 2012;xx(x):xxx

Pulmonary Hypertension in CKD

forms of pulmonary hypertension from 1980-2002documented that the death rate in patients with pulmo-nary hypertension during these 2 decades was stable,ranging from 5.2-5.4 deaths/100,000.15,16

PatientsWithCKD

The prevalence of pulmonary hypertension in pa-tients with CKD is difficult to estimate preciselybecause epidemiologic data for this disorder in pa-tients with CKD are scarce and based mainly onretrospective data and/or small studies with method-ological limitations. Although an international groupof experts recommended that the diagnosis of pulmo-nary hypertension should be based on right-sidedcardiac catheterization and defined as the presence ofmean pulmonary artery pressure �25 mm Hg,2 onlyone study has measured PASP with invasive methodsin patients with CKD.17 In most studies of patientswith CKD, pulmonary artery pressure has been esti-mated as Doppler-derived PASP, but there is no unifor-mity in diagnostic criteria. Various PASP cutoffs havebeen applied, ranging from 25 to �45 mm Hg,18-37

and in one study, TRV �2.5 m/s was adopted as themajor criterion to make the diagnosis of pulmonaryhypertension.19

The variability of the criteria adopted in these studiesexplains the wide range of the reported prevalence ofpulmonary hypertension in patients with CKD and hin-ders crude comparisons among studies (Table 2). Ofnote, no data for the prevalence of pulmonary hyperten-sion in patients with CKD stages 1-3 currently areavailable. In about half the studies of patients withCKD, PASP was estimated after creation of an arterio-venous fistula (AVF), which itself may provoke pulmo-nary hypertension (discussed later). In patients withnon–dialysis-dependent CKD stage 5 (NDD-CKD5),the prevalence of pulmonary hypertension ranges from9%-39%18,21-24 (Fig 1). Thus, NDD-CKD5 is a condi-tion with a prevalence of pulmonary hypertension thatis about 2-8 times higher than in the general popula-tion. Figure 1 also shows the prevalence of pulmonaryhypertension in relation to various diagnostic cutoffsand CKD stages. As expected, the prevalence ofpulmonary hypertension is related inversely to thepulmonary pressure cutoff. Furthermore, pulmonaryhypertension prevalence is higher in the dialysis popu-lation than in patients with NDD-CKD5. In the onlystudy that measured pulmonary artery pressure byright-sided cardiac catheterization,17 pulmonary hyper-tension was observed in 81% of hemodialysis (HD)patients and 71% of patients with CKD stages 4-5.The very high prevalence in this study arises becauseit enrolled only individuals with dyspnea that wasunexplained by other causes, as opposed to previous

studies involving unselected populations. In this se-

Am J Kidney Dis. 2012;xx(x):xxx

lected population, the prevalence of pulmonary arteryhypertension (WHO class I) was 6% in patients withCKD stages 4-5 and 13% in HD patients, and theprevalence of WHO class II pulmonary hypertensionwas 71% and 65%, respectively. Of note, in HDpatients, pulmonary artery hypertension was un-masked by studies that were performed after dialysis.Thus, these findings suggest that pulmonary arteryhypertension should be suspected in both dialysispatients and patients with NDD-CKD4-5 if they haveunexplained dyspnea, and they further suggest thatdiagnostic studies by right-sided cardiac catheteriza-tion in HD patients should be made after dialysis.

Most studies of patients with CKD were performedin Middle Eastern populations18,20,22-31,37; limited in-formation is available regarding CKD populations inother countries.19,21,32-36 In 5 studies performed in theUnited States,19,21,34-36 the prevalence of pulmonaryhypertension ranged from 25%-47%; values weremore consistent (32%-42%) in the 4 studies thatadopted an identical diagnostic cutoff (Doppler-derived PASP �35 mm Hg).21,34-36

For the relationship between pulmonary hyperten-sion and dialysis type, Fig 1 shows that the prevalenceof pulmonary hypertension is lower in patients treatedwith peritoneal dialysis (PD; 0%-42%) than HD(18.8%-68.8%).25,30-33,35-37 In studies that directly com-pare patients with CKD stage 5 at the same institutionwho are treated with HD with those treated with PD andthat take into account the presence of a fistula, pulmo-nary hypertension was much less frequent in PD pa-tients.23,25,30,33 After kidney transplantation, pulmo-nary hypertension often is related to the evolution ofassociated LV disorders; that is, pulmonary hyperten-sion frequently improves in patients who exhibit im-proved LV function.20,32 No data currently are avail-able comparing clinical outcomes in patients withCKD stage 5 with and without pulmonary hyperten-sion. However, observations in a cohort of 500 pa-tients with WHO class I pulmonary hypertension39

suggest that CKD conveys a higher risk of pulmonaryhypertension. In this cohort, elevated serum creatininelevels were associated with higher right atrial pres-sure, lower cardiac index, and increased death risk.

Information about the impact of pulmonary hyper-tension on clinical outcomes in patients with kidneydisease on HD therapy was gathered in only 4 cohortstudies.18,19,23,36 Two18,23 are based largely on thesame cohort, but had different patient accrual andused different diagnostic criteria. In the first analysisof 58 patients in this cohort,23 patients with Doppler-derived PASP �35 mm Hg had a higher mortality rate(30.8%) compared with those with PASP �35 mm Hg

(3.5%). In the second analysis, which investigated

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Bolignano et al

Table 2. Studies of PH in Patients With CKD

Study Country N PH Criteriaa

PH Prevalence(%) Notes

StudyQualityb

PH in CKD5

Pabst17 (2012)c DE 31 mPASP �25 71 PAH (WHO I) in 6% and WHO II in 71% Medium

Yigla18 (2009) IL 127 ePASP �45 13.4 PH before HD initiation associated withhigher risk of death (HR, 3.6)

Good

Issa21 (2008) US 215d ePASP �35 25 PASP �50 independently associatedwith reduced post-Tx survival (HR,3.75)

Medium

Abdelwhab22

(2008)EG 31 ePASP �35 32.3 Mean PASP significantly higher in HD

pts than CKD ptsMedium

Yigla23 (2003) IL 12 ePASP �35 8.3 After HD initiation, PH developed in 2/3of CKD pts with initially normal PASP

Medium

Havlucu24 (2007) TR 23 ePASP �35 39.1 44% of CKD pts with PH had an AVF Medium

PH in CKD5D

Pabst17 (2012)c DE 31 HD mPASP�25 8 PH (WHO II) in 77% and WHO I in 13%;significant post-HD decrease inmPAP and PCWP

Medium

Yigla18 (2009) IL 127 HD ePASP �45 29.1 PH after HD initiation associated withhigher risk of death (HR, 2.4)

Good

Ramasubbu19

(2012)US 90 HD TRJ �2.5 m/s 47 After 12 mo, pts with PH had increased

mortality (26%) vs those without (6%)Good

Nakhoul20 (2005) IL 42 HD ePASP �25 (atrest) or �30(with exercise)

48 Higher cardiac output and lowercirculating levels of NO metabolitesin pts with PH vs those without

Medium

Issa21 (2008) US 215 NDD-CKD/HD/PDd ePASP �35 32 No difference in mean PH in HD vs PDpts; PASP �50 independentlyassociated with reduced post-Txsurvival (HR, 3.75)

Medium

Abdelwhab22

(2008)EG 45 HD ePASP �35 44.4 PASP correlated with AVF blood flow,

pro-BNP, and LVDDMedium

Yigla23 (2003) IL 58 HD; 5 PD ePASP �35 39.7 HD; 0 PD Higher mortality rate in HD pts with PH(30.8%) vs those without (3.5%)

Medium

Havlucu24 (2007) TR 25 HD ePASP �35 56 PASP correlated directly with AVF flowand duration and inversely withresidual urine volume

Medium

Bozbas25 (2009) TR 432 HD; 68 PD ePASP �30 18.8 HD; 5.9 PD No differences in prevalence of COPD,asthma, smoking, HTN, and DM inpts with vs without PH

Medium

Yigla26 (2004) IL 49 HD ePASP �35 57.1 No correlations between severity ofpulmonary calcifications and PH

Good

Amin27 (2003) EG 51 HD ePASP �35 29 No correlations between PH and PTHlevels or pulmonary calcifications

Medium

Tarrass28 (2006) MA 86 HD ePASP �35 26.7 No correlations between PH and PTHlevels

Low

Mahdavi-Mazdeh29

(2008)IR 62 HD ePASP �35 51.6 Hb and albumin levels significantly

lower in pts with PHLow

Etemadi30 (2011) IR 278 HD; 145 PD ePASP �35 41.1 HD; 18.7 PD Serum iron and Hb levels significantlylower in pts with PH

Low

Unal31 (2009) TR 135 PD ePASP �35 12.6 PASP independently associated withECW and LVMI

Medium

Casas-Aparicio32

(2010)MX 35 HD ePASP �40 48.6 After kidney Tx, LVF and ePASP

significantly improved and PHprevalence decreased to 15.3%

Medium

Fabbian33 (2011) IT 29 HD; 27 PD ePASP �35 58.6 HD; 18.5 PD PH independently associated withdialysis vintage and DBP

Low

(Continued)

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Pulmonary Hypertension in CKD

127 patients in the same cohort,18 pulmonary hyperten-sion (here defined as Doppler-derived PASP �45 mmHg) was an independent risk factor for death whetherit was detected before initiating dialysis therapy orafter beginning regular HD treatment (hazard ratios[HRs] of 3.6 and 2.4, respectively). In the thirdstudy19 of 90 maintenance HD patients with AVFs,pulmonary hypertension (defined as TRV �2.5 m/s)was explained by impaired left systolic ventricularfunction and elevated pulmonary capillary wedgepressure. Furthermore, mortality was 4-fold higher inpatients with pulmonary hypertension (26% per year)compared with those without pulmonary hypertension(6%). Finally, in a very recent study,36 pulmonaryhypertension had a 38% prevalence in a cohort of 228HD patients and conveyed a high risk of death (HR,2.17; 95% confidence interval, 1.31-3.61; P � 0.01)in adjusted analyses. Of note, in a study of 215patients on maintenance dialysis therapy, the presenceof pulmonary hypertension before kidney transplanta-tion predicted risk of death after transplantation, which

Table 2 (Cont’d). Studie

Study Country N PH Criteria

Zlotnick34 (2010) US 55 HD ePASP �35

Kumbar35 (2007) US 36 PD ePASP �35

Agarwal36 (2011) US 288 HD ePASP �35

Kiykim37 (2010) TR 74 HD ePASP �30

Note: Search strategy and selection process are provided informerly was referred to as precapillary PH; class II, as postcapill

Abbreviations: AVF, arteriovenous fistula; Ca � P, calciumdisease; CKD5(D), chronic kidney disease stage 5 (treated by diblood pressure; DE, Germany; DM, diabetes mellitus; ECW, epressure (echocardiography); Hb, hemoglobin; HD, hemodialysLVDD, left ventricular diastolic dysfunction; LVF, left ventricularmeasured pulmonary artery pressure (by right-sided cardiac cathkidney disease; NO, nitric oxide; PAH, pulmonary artery hypertewedge pressure; PD, peritoneal dialysis; PH, pulmonary hypeparathyroid hormone; TRJ, tricuspid regurgitation jet; TR, Turkey

aValues are given in mm Hg.bBecause studies with different designs were appraised,

completeness of reporting of title/abstract, introduction, methoSTROBE checklist of 22 items.38 Good quality indicates moraddressed; and low quality, fewer than 5 items.

cThis study enrolled only patients in WHO functional class highhad CKD stage 4 (exact number not reported).

dThis retrospective study analyzed data from 215 transplant canumber of patients in those subcategories was not specified.

suggests that transplantation may not reverse the

Am J Kidney Dis. 2012;xx(x):xxx

excess risk associated with established pulmonaryhypertension.21 Large prospective studies adoptingwell-standardized criteria including right-sided car-diac catheterization are needed to assess the risk ofdeveloping pulmonary hypertension in patients withNDD-CKD5 and dialysis patients. Importantly, thesestudies should specifically assess whether pulmonaryhypertension is a corollary to concomitant LV disor-ders but by itself has only a modest direct impact onclinical outcomes or whether pulmonary hypertensionrepresents a truly independent risk factor for deathand adverse cardiovascular outcomes for patients withCKD. Furthermore, epidemiologic studies that specifi-cally focus on the members of CKD population whoare receiving conservative treatment and do not havean AVF are required to assess the potential impact ofpulmonary hypertension on clinical outcomes indepen-dently of pre-existing cardiovascular or pulmonarydiseases. Well-designed intervention studies are neededin both dialysis patients and those with NDD-CKD todefinitively establish whether pulmonary hyperten-

H in Patients With CKD

PH Prevalence(%) Notes

StudyQualityb

38 PH in HD pts associated with increasedrisk of early graft dysfunction

Medium

42 PASP correlated with serumphosphorus and PTH levels, andCa � P

Low

38 In multivariate analyses, PH anindependent predictor for all-causemortality (HR, 2.17; 95% CI, 1.31-3.61; P � 0.01)

Good

68.8 Decrease in pulmonary artery pressureafter HD with high-flux polysulfonemembrane

Low

S1 (available as online supplementary material). Class I PHH.phorus product; CI, confidence interval; CKD, chronic kidney); COPD, chronic obstructive pulmonary disease; DBP, diastolicellular water; EG, Egypt; ePASP, estimated pulmonary artery, hazard ratio; HTN, hypertension; IL, Israel; IR, Iran; IT, Italy;

tion; LVMI, left ventricular mass index; MA, Morocco; mPASP,ation); MX, Mexico; NDD-CKD, non–dialysis-dependent chronic, PASP, pulmonary artery pressure; PCWP, pulmonary capillaryion; pro-BNP, pro–B-type natriuretic peptide; pt, patient; PTH,transplantation; WHO, World Health Organization.

evel classification of quality was developed considering theesults, discussion, and other information, as indicated in then 15 items correctly addressed; medium quality, 5-15 items

an II with dyspnea unexplained by other causes. Some patients

tes, including those with CKD5 and CKD5D (HD/PD). The exact

s of P

a

Itemary P-phosalysisxtracis; HRfunc

eteriznsionrtens; Tx,

a 3-lds, re tha

er th

ndida

sion in CKD represents a modifiable risk factor.

5

ialys

Bolignano et al

RISK FACTORS FOR PULMONARY HYPERTENSIONIN PATIENTS WITH CKD

Overview

There are no proper longitudinal studies detailingthe natural history of pulmonary hypertension in CKD,from its early stages to kidney failure. The factorsresponsible for pulmonary hypertension in patientswith NDD-CKD5 and HD patients, particularly altera-tions that influence the control of vascular tone in thelung, are poorly defined. As previously reported, mostcases of pulmonary hypertension in patients withCKD are classified as WHO class II.17 In these pa-tients, pulmonary wedge pressure is �15 mm Hg anddepends on associated LV disorders. WHO class I, forwhich pulmonary wedge pressure is �15 mm Hg, iscaused by high arteriolar tone similar to that ofidiopathic forms of pulmonary artery hypertension orpulmonary artery hypertension secondary to systemicdisorders such as scleroderma. This section discussesa list of factors for which the role in pulmonaryhypertension in patients with CKD has been reason-ably well assessed. Most patients with CKD areaffected by one or more comorbid conditions that bythemselves may induce and/or exacerbate pulmonaryhypertension, with the particular mechanism(s) vary-ing according to the patient’s concomitant LV disor-ders. Furthermore, as discussed next, CKD and HDtreatment may trigger other risk factors acting at the

Figure 1. Prevalence of pulmonary hypertension (PH) in exkidney disease (CKD) stage. Reference numbers are indicatednon–dialysis-dependent chronic kidney disease; PD, peritoneal d

precapillary level.

6

LVDisorders, VolumeOverload, andLungDisease

Hypertension and diabetes mellitus, 2 dominantcauses of kidney disease, trigger LV diastolic dysfunc-tion, an alteration bound to increase pulmonary ve-nous and arterial pressure.40 Chronic volume over-load, a factor implicated in LV disorders and in thehigh venous return in patients with CKD, may inducepulmonary venous hypertension by both increasingpulmonary blood flow and adversely affecting LVfunction. In addition, myocardial stiffness secondaryto myocardial infarction, another frequent complica-tion of CKD, may contribute to pulmonary hyperten-sion. In categorical terms, patients with LV disordersand/or volume overload constitute group II of theWHO classification, whereas patients with lung dis-eases, either restrictive (ie, obese patients with CKD)or obstructive (ie, patients with chronic obstructivepulmonary disease), are grouped in WHO class III.2

In chronic obstructive pulmonary disease, the mainmechanism underlining increased pulmonary pressureis chronic hypoxia, a potent pulmonary vasoconstric-tor.41 If sustained, vasoconstriction in the lung leadsto extensive remodeling of the pulmonary vessels anda steady reduction in vessel compliance, a phenom-enon which in and of itself contributes to pulmonaryhypertension.42

Pulmonary capillary wedge pressure is consideredto be a reliable marker for LV end-diastolic pressure.However, determining whether left-sided cardiac dis-ease is present on the basis of pulmonary capillary

studies in relationship to (A) diagnostic cutoffs and (B) chronict to cutoff points. Abbreviations: HD, hemodialysis; NDD-CKD,is.

istingnex

wedge pressure is unreliable in patients with pulmo-

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Pulmonary Hypertension in CKD

nary hypertension because �50% of patients who areconsidered to have pulmonary artery hypertension onthe basis of pulmonary capillary wedge pressure even-tually may turn out to have WHO class II pulmonaryhypertension instead when diagnosed on the basis ofLV end-diastolic pressure.43 Thus, when there is achoice between pulmonary capillary wedge pressureand LV end-diastolic pressure in a patient with pulmo-nary hypertension, LV end-diastolic pressure shouldbe regarded as the gold standard for the diagnosticdefinition of pulmonary hypertension.

Arteriovenous Fistula

AVFs, be they the result of trauma or intentionallycreated, have profound hemodynamic effects. An AVFleads to decreased systemic vascular resistances, en-hanced venous return, and increased cardiac output tomaintain proper blood flow to all organs and tissues.These adaptations increase pulmonary blood flow andset the stage for pulmonary hypertension. Becausepressure is the product of flow and resistance, in-creased pulmonary flow necessarily leads to increasedpressure at any level of pulmonary vascular resis-tance. Well-performed studies show that pulmonarypressure increases in strict temporal relationship withAVF creation44 and that pulmonary hypertension tendsto worsen over time in this population.24,33 Accord-ingly, in HD patients, AVF flow and AVF duration arerelated independently to the severity of pulmonaryhypertension.22 AVF compression by a sphygmoma-nometer20,23,26 or surgical AVF closure45 induces arapid decrease in mean cardiac output followed by astable decrease in pulmonary pressure. As discussed,AVFs may explain in part why the prevalence of

Figure 2. Main mechanisms pro-posed to explain the pathogenesis of pul-monary hypertension (PH) in patients withchronic kidney disease. Abbreviations:AV, arteriovenous, COPD, chronic ob-structive pulmonary disease; LV, left ven-

tricular.

Am J Kidney Dis. 2012;xx(x):xxx

pulmonary hypertension is higher in HD patients thanin PD patients.23,30,33

Exposure toDialysisMembranes

Neutrophil activation secondary to blood–dialysismembrane contact accompanied by reversible neutro-phil sequestration in the lung, a phenomenon that wasintensively investigated in the 1980s,46,47 contributesto causing or worsening microvascular lung disease inHD patients.48 This phenomenon is particularly pro-nounced when dialysis is performed using cellulosicmembranes and is attenuated but not abolished withsynthetic and modified cellulosic membranes. In acrossover trial of a series of 74 patients without anAVF who were dialyzed through a central venouscatheter, use of high-flux polysulfone filters was asso-ciated with a more pronounced decrease in postdialy-sis pulmonary pressure than the use of celluloseacetate filters.37 The hypothesis that volume overloadand LV disorders triggered or exacerbated by kidneydisease and repeated exposure to dialysis membranesmay cause pulmonary hypertension independently ofthe AVF and other factors is supported by the demon-stration that kidney transplantation may revert pulmo-nary artery pressure to normal in patients who stillhave a functioning AVF.20

SystemicDiseasesAssociatedWithCKD

Pre-existing connective tissue diseases and superim-posed infectious, hematologic, and liver diseases canall contribute to pulmonary hypertension in patientswith CKD by mechanisms that interfere with thecontrol of microvascular tone in the lung (WHO classI; Fig 2). However, collectively, these factors largely

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Bolignano et al

fail to explain the high prevalence of pulmonaryhypertension in dialysis patients because most pa-tients with CKD exhibit pulmonary hypertension evenin the absence of these diseases.48

Endothelial Dysfunction

Endothelial dysfunction is a main trigger of pulmo-nary hypertension.49 This link is even more relevantin pulmonary hypertension in patients with CKD, inwhom endothelial dysfunction is pervasive.50 Theimpaired capacity of the endothelium to regulatevascular tone in patients with CKD depends on animbalance between vasoconstrictors (eg, high levelsof endothelin 1) and vasodilators (reduced generationof nitric oxide [NO]).49,51 The role of endothelialdysfunction in HD patients with pulmonary hyperten-sion is supported by cross-sectional findings thatshow that plasma NO levels are decreased in HDpatients with pulmonary hypertension compared withthose without pulmonary hypertension and by theobservation that HD treatment increases NO levels inpatients without pulmonary hypertension to a greaterextent than in those with pulmonary hypertension.26

In this respect, asymmetric dimethylarginine (ADMA),an endogenous inhibitor of NO synthase that is synthe-sized abundantly at lung level52 and that accumulatesin CKD,53 has been implicated strongly in experimen-tal54 and primary55 forms of pulmonary hypertension.ADMA attains very high concentrations in patientswith kidney disease.53 Thus, ADMA is a prime uremictoxin potentially implicated in pulmonary hyperten-sion in this population.

Sleep-DisorderedBreathing

Sleep apnea is a factor of paramount importance forthe high risk of pulmonary hypertension in the settingof CKD. Episodes of nocturnal hypoxia, the keypathophysiologic effect of sleep apnea, are frequent inpatients with CKD regardless of whether they aredialysis dependent.56,57 As we discuss next, volumeoverload is a major factor in sleep apnea, particularlyin patients with kidney disease. Nocturnal hypoxemiaarising from sleep apnea is a strong trigger of pulmo-nary hypertension in experimental models,58 and aclose link between oxygen saturation and pulmonaryartery pressure has been established in clinical physi-ology experiments in both healthy persons and pa-tients with chronic obstructive pulmonary disease.59

Sympathetic activation is the main mechanismwhereby hypoxemia increases pulmonary pressure.60

In this respect, it is interesting to note that patientswith sleep-disordered breathing have increased ADMAlevels.61 Furthermore, circulating levels of this NOsynthase inhibitor are associated with sympathetic

nerve activity (as assessed by measurements in the

8

peroneal nerve) in patients with CKD62 and withnorepinephrine levels in dialysis patients.63 Given thestrong vasoconstriction potential of ADMA in thelung vasculature and the observation that sympatheticnervous system activity and ADMA seem to share acommon pathogenic pathway that is conducive to LVhypertrophy62 in patients with CKD and to cardiovas-cular events in dialysis patients,64 it appears possiblethat the same pathogenic pathway be implicated inpulmonary hypertension in these patients.

Risk Factors Specific toCKD

PASP was related directly to pulse and systolicpressure, as well as to age, in the Olmsted study,which suggests that in the community setting, pulmo-nary artery stiffening may have a role in pulmonaryhypertension.8 As part of a systemic phenomenon,arterial rigidity is increased in patients with CKD andcalcium deposits can be demonstrated in the pulmo-nary artery in patients with kidney disease, thus impli-cating arterial stiffness in pulmonary hypertension inthis population.65 Stiffness aside, experimental stud-ies in dogs show that parathyroid hormone levels mayincrease pulmonary resistances.66 However, 2 indepen-dent studies in patients with kidney disease26,27 failedto show an association between severity of pulmonarycalcifications and parathyroid hormone level. Further-more, parathyroid hormone levels do not differ be-tween patients with and without pulmonary hyperten-sion.27 Severe anemia is an established cardiovascularrisk factor in CKD and its impact on the cardiovascu-lar system extends to pulmonary circulation becauselow hemoglobin levels can contribute to pulmonaryhypertension by aggravating hypoxia triggered byconcomitant conditions.67

TREATING PULMONARY HYPERTENSION INPATIENTS WITH CKD

The treatment of pulmonary hypertension in pa-tients with CKD has not been investigated in specificstudies to date. The high prevalence of LV disorders inpatients with CKD probably explains why most casesof pulmonary hypertension in this population areWHO class II.17 In the absence of specific studies,recommendations for the treatment of WHO class IIpulmonary hypertension in the general population66

also can be extended provisionally to patients withCKD. In particular, treating underlying LV disordersappears fundamental in both patients with NDD-CKD5 and dialysis patients. Careful attention to opti-mizing body fluid volume in patients with CKD bydiuretics, reducing dietary salt intake, and/or appropri-ate dialysis treatment intensification cannot be overem-phasized. In patients with CKD with WHO class II

pulmonary hypertension (pulmonary hypertension sec-

Am J Kidney Dis. 2012;xx(x):xxx

Pulmonary Hypertension in CKD

ondary to LV disorders), vasodilator therapy, whichcurrently is recommended for WHO class I patients,68

should be avoided because it potentially is harmful. Arandomized trial testing epoprostenol in 471 patientswith pulmonary hypertension and severe LV dysfunc-tion69 was terminated early due to an increase inmortality.

As discussed, sleep apnea, a frequent complicationin patients with NDD-CKD5 and dialysis patients, is apotent trigger of pulmonary hypertension. Thus, sleepapnea should be suspected and systematically investi-gated in patients with CKD with high PASP. Sleepapnea is attributed in large part to edema in thehypopharynx (rostral edema). Supine position andhypopharynx relaxation during nocturnal sleep aggra-vate rostral edema.70 Reducing or correcting volumeexcess by PD71 or by intensifying HD72 produces adramatic improvement in sleep apnea. However, westill have no proof that this translates into a meaning-ful decrease in PASP in dialysis patients. Based onobservations in patients with other forms of sleepapnea, it seems likely that such treatment would havea beneficial effect on pulmonary hypertension in dialy-sis patients. In patients with pulmonary hypertensionand high AVF flow, interventions aimed at reducingAVF flow may be considered when clinically indi-cated.

As we have discussed, in symptomatic HD patients,repeated exposure to dialysis membranes may ad-versely affect lung microcirculation,38 and the highfrequency of pulmonary artery hypertension in symp-tomatic dialysis patients18 further supports this possi-bility. In dialysis patients with persisting pulmonaryhypertension after volume overload has been cor-rected and LV disorders have been treated adequately,right-sided cardiac catheterization and measurementof pulmonary wedge pressure will determine whetherthe clinical assessment is accurate and can distinguishwhether further treatment for volume overload and/orLV dysfunction is needed or if treatment directed atpulmonary artery hypertension is indicated. In pa-tients with CKD with WHO class I pulmonary arteryhypertension, specific approved therapies may be con-sidered based on the individual’s risk-benefit pro-file.68

CONCLUSIONS

Pulmonary hypertension is prevalent in patientswith CKD, particularly in patients with stage 5 main-tained on HD. Pulmonary hypertension in patientswith CKD potentially is a reversible process because,along with associated LV disorders, it may regressafter kidney transplantation. Several risk factors, in-cluding LV dysfunction, sleep apnea, AVFs, and an

imbalance between endogenous vasoconstrictor and

Am J Kidney Dis. 2012;xx(x):xxx

vasodilator substances, are implicated in pulmonaryhypertension in patients with CKD. Pulmonary hyper-tension has been associated with a higher risk of deathin 4 small cohort studies involving patients withNDD-CKD5 and dialysis patients. In dialysis patientswith established pulmonary hypertension, the excessrisk of death may persist after kidney transplantation.Only with large prospective studies that use standard-ized criteria and perform right-sided cardiac catheter-ization can the true risk of pulmonary hypertension beassessed in patients with NDD-CKD5 and dialysispatients.

ACKNOWLEDGEMENTSWith the exception of L. Gargani, the authors constitute

EURECA-m (European Renal and Cardiovascular Medicine), aworking group of the ERA-EDTA (European Renal Association–European Dialysis Transplantation Association).

Support: None.Financial Disclosure: The authors declare that they have no

relevant financial interests.

SUPPLEMENTARY MATERIALItem S1: Search strategy and selection process.Note: The supplementary material accompanying this article

(http://dx.doi.org/10.1053/j.ajkd.2012.07.029) is available atwww.ajkd.org.

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